Engineering New Technologies Based on Multicellular and Inter-kingdom Signaling (MIKS) Awards

The Emerging Frontiers in Research and Innovation (EFRI) office awarded 14 grants in FY 2011, including the following 8 on the topic of Engineering New Technologies Based on Multicellular and Inter-kingdom Signaling (MIKS):

Controlling colon cancer cells
The project “NOTCH Signaling in Colon Cancer Stem Cells” (1137269) will be led by Michael Elowitz of the California Institute of Technology, in collaboration with Steven Lipkin of Weill Cornell Medical College, Xiling Shen of Cornell University, and Ron Weiss of the Massachusetts Institute of Technology.

Conventional therapies for stopping the runaway growth of cancerous colon stem cells are largely ineffective.  Cancer’s reckless cell division is initiated by internal and external signals.  This research team will create devices for tracking colon stem cell behavior over time, design mathematical models of the decision circuits that determine how cells respond to signals, and engineer synthetic genetic circuits to understand and test fundamental design principles that govern when a normal stem cell becomes a stem cell cancer.   With better understanding of how signals of normal stem cells and cancerous stem cells control self-renewal, differentiation, and homeostasis, a targeted therapy for colon cancer stem cells may be possible. 

Constructing a microbe “pill”
The project “Control of Signaling and Function by Design with Spatially Pre-structured Microbial Communities” (1137089) will be led by Rustem F. Ismagilov of the California Institute of Technology, in collaboration with Alexander Chervonsky of the University of Chicago, Christopher Henry of University of Chicago and Argonne National Laboratory, Sarkis Mazmanian of the California Institute of Technology, and Folker Meyer of University of Chicago and Argonne National Laboratory.

The goal of this project is to use understanding of inter-species and inter-kingdom signaling to engineer spatially structured microbial communities within a biocompatible material that could serve as a “pill” to preserve and/or restore microbial balance.  The team will develop methods to predict which microbes and which configuration will best achieve the desired effects.  They will develop technologies and design principles to understand the signaling and responses involved and how they are affected by spatial structure.

Deciphering microbe communications
The project “Microfluidic-based Screening of Multi-Kingdom Microbial Communication Molecules” (1136903) will be led by Nancy Keller of the University of Wisconsin, Madison, in collaboration with Clay Wang of the University of Southern California, and with David Beebe and Anna Huttenlocher of the University of Wisconsin, Madison.

Bacteria and fungi often share an environment, whether among plant roots or within an animal’s lung.  This research team will investigate how the bacterial and fungal cells in a shared environment interact with and affect each other through their molecular signals.   To quickly capture and analyze signal molecules, the researchers plan to create novel microscale devices that offer robust and precise control of the experimental environment.  Ultimately, the researchers aim to create broadly applicable methods to understand the molecular language between cells from many different biological kingdoms.  

Stressing and straining cells
The project “Force Sensing and Remodeling by Cell–Cell Junctions in Multicellular Tissues” (1136790) will be led by Beth L. Pruitt, with colleagues Alexander R. Dunn, W. James Nelson, and William I. Weis, all of Stanford University.

This project will investigate mechanical interactions between cells that are instrumental to basic processes of life and yet remain poorly understood.   In multicellular tissues, the effects of mechanical forces such as stress and strain are focused on junctions that connect the cells together.  The team will create novel engineering devices to visualize and characterize how junctions between living cells change as force is applied.  They will also use a new class of molecular force sensors to directly visualize the transmission of molecular-scale mechanical force through cell junctions.  With these methods, devices, and probes, this project aims to transform understanding of the thresholds and mechanisms for environmental adaptation and remodeling of multicellular systems.

Signaling in biofilms
The project “Deciphering and Controlling the Signaling Processes in Bacterial Multicellular Systems and Bacteria–Host Interactions” (1137186) will be led by Dacheng Ren, with colleagues Rebecca Bader, Yan-Yeung Luk, Radhakrishna "Suresh" Sureshkumar, and Roy Welch, all from Syracuse University.

Bacterial colonies are known to tolerate antibiotics and disinfectants by turning into biofilms and by sending some cells, known as persister cells, into a dormant state.  How bacterial signaling and environmental/host factors affect a biofilm’s tolerance and persister cell distribution are unknown. The goal of this project is to understand and manipulate the signaling processes in such systems, in order to provide better options for bacterial control.  The team will systematically characterize persister formation during biofilm development, and they will identify the roles of genes and signaling processes in persister formation.  These findings will enable the researchers to accurately model and predict biofilm signaling and to create nanoparticles that disrupt the formation of persister cells.   

Shaping fruit fly formation
The project “Multiscale Analysis of Morphogen Gradients” (1136913) will be led by Stanislav Y. Shvartsman of Princeton University, in collaboration with Hang Lu of the Georgia Institute of Technology, Christine Rushlow of New York University, and Saurabh Sinha of the University of Illinois at Urbana–Champaign.

What controls the spatial and temporal patterns of gene expression and cell differentiation?  This project will investigate the concept of morphogen gradients, which are concentration profiles of molecules that provide dose-dependent control of gene expression.  With the help of microfluidics-based imaging of numerous fruit fly embryos, the research team will quantify patterning signals and gene expression, which differ with time and place.  These results will enable the researchers to create models of pattern formation to elucidate general principles behind the operation of genetic and multicellular networks.  Ultimately, this work will help explain embryo development and provide guidelines for tissue engineering and regenerative medicine. 

Learning from termites
The project “Creation and Manipulation of an Artificial Termite Gut through Control of the Microenvironment” (1137249) will be led by Ranjan Srivastava, with colleagues Daniel Gage, Joerg Graf, William Mustain, and Leslie Shor, all from the University of Connecticut.

Microbes from three kingdoms live symbiotically within the lower termite gut, where they coordinate chemical processes that are beyond the capability of any one organism.  The composition and function of the microbial community changes with even tiny variations in the physical and chemical habitat of the termite gut.  This project will investigate the changing capabilities of the termite gut community to break down various carbon sources, such as lignocelluloses, and its self-regulation through a complex signaling network.  To do so, the researchers will systematically replicate micro-scale physical and chemical features of a lower termite gut using engineered microhabitats.  By understanding microorganisms’ signaling processes, it may be possible to manipulate microbial communities and harness their capabilities for chemical production on an industrial scale. 

Engineering structures with many cells
The project “Harnessing Intercellular Signaling to Engineer Pattern Formation” (1137266) will be led by Jeffrey Tabor of William Marsh Rice University, in collaboration with Oleg Igoshin of Rice, and with Benjamin Kerr, Eric Klavins, and Georg Seelig of the University of Washington.

The growth of complex organisms requires the formation of complex multicellular patterns and structures.  How large numbers of noisy and error-prone cells coordinate their actions over space and time remains a mysterious process.  This project will take an engineering approach to understanding and controlling pattern formation using a synthetic “developmental” system.  Long-term, the goal is to create an automated framework for designing genetic networks that cause a cell to grow into a desired multicellular pattern or structure.

Summaries of the Projects on Mind, Machines, and Motor Control (M3C)

 

- Cecile J. Gonzalez, NSF, cjgonzal@nsf.gov -